SARS-CoV-2-Specific IgG Levels Are Inversely Associated with ACPA-Reactive Pathological and Natural Autoantibody Profiles in Residual Diagnostic Samples

Background/Objectives: SARS-CoV-2-specific antibody levels vary among patients with systemic autoimmune rheumatic diseases (SARDs). In rheumatoid arthritis (RA), the most prevalent SARD, this is further shaped by rheumatoid factors (RFs). Attenuated post-vaccination antibody levels in RA are documented, but links to broader autoreactivity remain underexplored. We therefore examined pathological (pAAbs) and natural autoantibodies (nAAbs) in relation to SARS-CoV-2-specific IgG. Methods: A decade-long dataset (2014–2024; 73,747 patients) gave descriptive context, not the substudy population. SARS-CoV-2 IgG and nAAbs were evaluated in 200 residual specimens collected between November 2023 and February 2024. SARS-CoV-2-specific IgG was interpreted as an antiviral readout, not a protection correlate (clinical/exposure data unavailable). QuantiVac (wild-type) and Omicron BA.1 IgG were compared across ACPA-reactive (n = 44/38), anti-SSA/SSB-dominant (n = 24/22), anti-dsDNA-reactive (n = 33/32), aPL AAb-dominant (n = 15/14), and autoantibody-negative groups (n = 70/68). Results: ACPA-reactive samples showed lower antiviral IgG across both assays. After age/sex adjustment, comparator groups had 2.58–3.30-fold higher QuantiVac and 2.70–4.87-fold higher Omicron BA.1 IgG. Antiviral IgG correlated inversely with ACPA IgG (ρ to −0.474) and RF isotypes (ρ = −0.299 to −0.400). ACPA-reactive samples showed increased CS-IgM and HSP60/HSP70 IgG/IgM reactivity, which correlated positively with ACPA IgG and RF isotypes. Conclusions: In this exploratory analysis, an ACPA-reactive serological profile was associated with lower SARS-CoV-2 IgG and higher, positively correlated CS- and HSP-directed autoantibody levels, suggesting a shared rather than independent basis for these autoreactive compartments. These cross-sectional associations persisted after age/sex adjustment but cannot be separated from unmeasured clinical, treatment, or exposure factors.